| TD Bank Grants in
Medical Excellence/Genesis Research Foundation Award
in the Department of Obstetrics and Gynaecology.
Dr. Venu Jain,
M.D., Ph.D., FRCSC, MRCOG
Clinical Fellow, Maternal-Fetal Medicine, Department
of Obstetrics & Gynaecology, Mount Sinai Hospital, The
University of Toronto
Thesis: Role
Of Gcm1 In Placental Development And Fetal Growth Restriction
Many serious
disorders of human pregnancy, including miscarriage,
fetal intrauterine growth restriction, and preeclampsia,
are believed to be caused by dysfunctional early placental
development. It is difficult to use human placentas
to understand the root causes of these disorders because
placentas become available for study after delivery
when the early events that underlie these disorders
are long past. However, it is now clear that placental
development in mice is remarkably similar to that of
humans. Indeed recent studies in genetically-altered
mice have shown that the genes important in placental
development are very similar between the two species.
We are particularly interested in one such gene - GCM1
- which when mutated to inhibit expression, was shown
to block placental development. Interestingly this gene
is also expressed in the human placenta, and low levels
of expression are associated with human fetal growth
restriction. However, whether low levels of GCM1 expression
is causing the disorder, or is merely correlated, is
not known.
The objective of the current study
is to use short inhibitory RNA (siRNA) to suppress expression
of GCM1 in the placenta to determine whether low levels
cause fetal growth restriction. If so, we will then
compare the placental pathology in this model with that
of human placentas from growth restriction pregnancies.
If the placental pathologies are similar, we can use
this model to advance our understanding of why the placentas
in human pregnancies with fetal growth restriction are
inadequately branched and fail to deliver adequate nutrition
to support normal fetal growth. If not, we can use this
novel approach to investigate the role of other genes
known to be critical for normal placental development.
In our studies, we will reduce GCM1
production during early placental development in the
embryonic stage in utero by injecting siRNA to GCM1
through fine glass-pulled pipettes positioned under
ultrasound guidance using an Ultrasound Biomicroscope.
We have preliminary results showing the efficacy of
this approach and are ready now to undertake a complete
study examining the dose-response relationship between
GCM1 expression and fetal and placental growth. We are
excited about the next phase of this project because
we will study the placenta later in gestation and will
for the first time observe the long term consequences
of inhibiting, but not abolishing, GCM1 expression in
early pregnancy.
These results will allow us to determine
how well this model mimics placental defects observed
in human placentas from growth-restricted placentas.
If similar, our long-term goal would be to use this
model to investigate methods to reverse these placental
defects thereby improving placental performance and
ultimately fetal growth and well being.
|
